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Support for Clinical Trials at NIMH

CollageIn 2014, NIH revised its definition of a clinical trial (see NOT-OD-15-015) and in 2016, launched a multi-faceted effort to enhance its stewardship over clinical trials (see NIH webpage on Clinical Trial Requirements for Grants and Contracts). All applicants conducting research on human subjects are encouraged to visit this webpage to better understand the definition of a clinical trial, new requirements for clinical trial research, and NIH strategies for implementation. Given the current NIH definition of clinical trials, some investigators are discovering that their human subjects research is now considered to fall under the NIH definition of a clinical trial and is subject to the NIH clinical trial requirements. This includes ‘Basic Experimental Studies with Humans’ (abbreviated BESH) which are studies that are defined as both “basic science research” and “NIH-defined Clinical Trials” (see below for more information).

For due dates on or after January 25, 2018, NIH requires that all applications involving one or more independent clinical trials be submitted through a Funding Opportunity Announcement (FOA) specifically designated as ‘Clinical Trial Required’, ‘Clinical Trial Optional’, or ‘Basic Experimental Studies with Humans’. The content below provides an overview of how the NIMH approaches its clinical trial portfolio and provides links to relevant NIMH FOAs that support clinical trial research. General inquiries regarding NIMH clinical trials and/or the clinical trial FOAs may be submitted to NIMHClinicalTrials@mail.nih.gov.

NIH Definition of a Clinical Trial

NIH defines a clinical trial as “A research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes” (NOT-OD-15-015). Go to NIH’s Definition of a Clinical Trial webpage to learn more and to find out if your study meets the NIH definition of a clinical trial.

NIMH FOAs to Address the Safety, Efficacy, and Effectiveness of Preventive, Therapeutic, and Services Interventions

NIMH solicits clinical trial applications through a series of FOAs that cover the intervention development pipeline, from first-in-human, early testing of new interventions, confirmatory efficacy trials, through to effectiveness trials. If the goal of the Clinical Trial application is to establish the safety, clinical efficacy, effectiveness, clinical management and/or implementation of preventive, therapeutic, or therapeutic interventions, the application must be submitted in response to one of the FOAs as outlined in the Clinical Trial Pipeline - Phase of Intervention Development below. Applications that involve clinical trials to establish safety, clinical efficacy, effectiveness, clinical management and/or implementation of interventions should NOT be submitted under the NIH Parent FOAs for Clinical Trials and if done so, will be returned without review.

NIMH requires an experimental therapeutics approach (see Clinical Trials – Applicant FAQs, Q1) for the development and testing of therapeutic, preventive, and services interventions, in which the studies do not only evaluate the clinical effect of the intervention, but also generate information about the mechanisms underlying a disorder or an intervention response. Studies proposed under these FOAs must clearly identify a target or mediator of the intervention being tested. A positive result will require not only that an intervention improves clinical outcomes, but that it also has a demonstrable effect on a target, such as a neural pathway, a key cognitive operation, interpersonal or contextual factor that is hypothesized to mediate the intervention’s effect, etc.

The NIMH FOAs for therapeutic, preventive, and services interventions support a wide range of intervention modalities: cognitive, behavioral, and other psychosocial approaches, psychopharmacological interventions, and interventions utilizing direct brain modulation/stimulation. The choice of targets, measures, and clinical endpoints will vary with the intervention modality. Applicants should carefully read the FOA to which they are responding and the Clinical Trials — Applicant FAQs for more detail on the expectations for specific intervention modalities. Applicants are strongly encouraged to contact a Scientific/Research Contact listed at the end of the relevant FOA to discuss the FOA and NIMH priorities.

Clinical Trial Pipeline - Phase of Intervention Development*
General Inquiries: NIMHClinicalTrials@mail.nih.gov
First in Human Exploratory Experimental Therapeutics Confirmatory Efficacy Effectiveness (Prevention, Treatment, Services)

First in Human and Early Stage Clinical Trials of Novel Investigational Drugs or Devices for Psychiatric Disorders (U01 - Clinical Trial Required)*

 

Pilot Effectiveness Trials for Treatment, Preventive and Services Interventions (R34 - Clinical Trial Required)

 

Early Stage Testing of Pharmacologic or Device-based Interventions for the Treatment of Mental Disorders (R61/R33 - Clinical Trial Required) and (R33 - Clinical Trial Required)*

Clinical Trials to Test the Effectiveness of Treatment, Preventive, and Services Interventions (R01 Clinical Trial Required) or (Collaborative R01 - Clinical Trial Required)

Development of Psychosocial Therapeutic and Preventive Interventions for Mental Disorders (R61/R33- Clinical Trial Required) and (R33 Clinical Trial Required)

Confirmatory Efficacy Clinical Trials of Non-Pharmacological Interventions for Mental Disorders (R01 Clinical Trial Required)

 

* The intent of the U01 and R61/R33 for drug development is to support early phase clinical trials to de-risk drug and device therapeutic candidates for further development.

First in Human and Early Stage Clinical Trials of Novel Investigational Drugs or Devices for Psychiatric Disorders

Scientific/Research Contact Information
General Inquiries: NIMHClinicalTrials@mail.nih.gov
Application Due Dates: Standard Dates Apply

Early Stage Testing of Pharmacologic or Device-based Interventions for the Treatment of Mental Disorders

Scientific/Research Contact Information
General Inquiries:
NIMHClinicalTrials@mail.nih.gov
Application Due Dates: February 15, 2019; June 15, 2019; October 15, 2019; February 14, 2020; June 15, 2020; October 15, 2020 for all application types (new, resubmission, and revision applications).

Development of Psychosocial Therapeutic and Preventive Interventions for Mental Disorders

Scientific/Research Contact Information
General Inquiries: NIMHClinicalTrials@mail.nih.gov
Application Due Dates: February 15, 2019; June 15, 2019; October 15, 2019; February 14, 2020; June 15, 2020; October 15, 2020 for all application types (new, resubmission, and revision applications).

Confirmatory Efficacy Clinical Trials of Non-Pharmacological Interventions for Mental Disorders

Scientific/Research Contact Information
General Inquiries: NIMHClinicalTrials@mail.nih.gov
Application Due Dates: February 15, 2019; June 15, 2019; October 15, 2019; February 14, 2020; June 15, 2020; October 15, 2020 for all application types (new, resubmission, and revision applications).

Pilot Effectiveness Trials for Treatment, Preventive and Services Interventions

Scientific/Research Contact Information
General Inquiries: NIMHClinicalTrials@mail.nih.gov
Application Due Dates: February 15, 2019; June 15, 2019; October 15, 2019; February 14, 2020; June 15, 2020; October 15, 2020 for all application types (new, resubmission, and revision applications).

Clinical Trials to Test the Effectiveness of Treatment, Preventive, and Services Interventions

Scientific/Research Contact Information
General Inquiries: NIMHClinicalTrials@mail.nih.gov
Application Due Dates: February 15, 2019; June 15, 2019; October 15, 2019; February 14, 2020; June 15, 2020; October 15, 2020 for all application types (new, resubmission, and revision applications).

Limited NIMH Participation on Parent Research Grant FOAs are to Accommodate Mechanistic Clinical Trials

NIMH utilizes the NIH Parent R01 Clinical Trial Required, the NIH Parent R21 Clinical Trial Required, the NIH Parent R01 Basic Experimental Studies with Humans, and the NIH Parent R21 Basic Experimental Studies with Humans to accept only “mechanistic” clinical trial applications (see below for descriptors of “mechanistic” clinical trials).

The Basic Experimental Studies with Humans (BESH) FOAs are parent FOAs for studies that fall within the NIH definition of a clinical trial and also meet the definition of basic research, as described in NIH Guide Notice NOT-OD-19-024. The NIH definition of basic research is consistent with that in the federal code (32 CFR 272.3), “the systematic study directed toward greater knowledge or understanding of the fundamental aspects of phenomena or of observable facts without specific applications towards processes or products in mind”.  The phrase “without specific application towards processes or products” refers to the application of biomedical or behavioral products, procedures, or services intended to improve the health status of the individual or a group of individuals either by better understanding the mechanism of action of an intervention or a measurable improvement in health.

Applicants proposing Basic Experimental Studies with Humans (BESH) are required to complete the full Human Subjects and Clinical Trial Information in the application form and to register and report results. However, NIH is delaying enforcement of registration and reporting requirements for BESH studies until September 2019 (NOT-OD-18-212).

NIH defines a mechanistic clinical trial as: "A mechanistic study is designed to understand a biological or behavioral process, the pathophysiology of a disease, or the mechanism of action of an intervention.” Additionally, NIMH supports mechanistic clinical trials that focus on biomarker studies that may provide information about physiological function, target engagement of novel therapeutics, and/or the impact of therapeutic responses. These types of studies do not have as a primary aim to establish the efficacy or effectiveness of the intervention.

NIMH consider two major categories of mechanistic trials (though there may be others):

  1. Mechanistic clinical trials using an intervention of known efficacy. These clinical trials utilize an efficacious intervention to investigate the pathophysiology, and/or psychopathology of mental disorders or the mechanisms of therapeutic responses; and to advance biomarkers of basic neurobiological processes. In such studies: (1) the primary aims do not involve establishing efficacy/effectiveness, and (2) the intervention chosen has already been demonstrated to have efficacy. These trials must be submitted under the NIH Parent R01 Clinical Trial Required, or the NIH Parent R21 Clinical Trial Required FOAs.
  2. Mechanistic clinical trials utilizing an experimental manipulation: These studies utilize an experimental manipulation and are primarily focused on understanding brain function in healthy individuals or those with disorders, by measuring responses to the experimental manipulation. Most of these mechanistic studies are expected to be responsive to the BESH FOAs (described above) since they are not intended to inform on the improvement of the health status of the individual or a group of individuals either by better understanding the mechanism of action of an intervention or a measurable improvement in health.

NIH Guide Notice NOT-MH-19-006 describe the types of clinical trials that NIMH will support under the NIH Parent Clinical Trial and BESH FOAs.

Selected Other Clinical Trial FOAs

NIMH also participates on selected FOAs that seek or allow clinical trial applications, some of which include other grant mechanisms than noted above. Applications submitted to NIMH via these FOAs are expected to comport with NIMH’s experimental therapeutics model.

These FOAs include:

  • Announcements from other NIH Institutes or Centers (on which NIMH participates)
  • Career (K) FOAs that accept independent clinical trials or Basic Experimental Studies with Humans (on which NIMH participates; see NIMH guidance for K applicants proposing Clinical Trials)
  • Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) FOAs

A current listing of these FOAs can be found on the  NIMH Funding Opportunities &  Announcements webpage.

Additional Resources for Applicants

Selected Publications

Published Guide Notices

  • NOT-MH-19-006 (December 21, 2018) - NIMH Acceptance of Clinical Trial Applications under the Parent R01 and R21 Clinical Trial Required, or Basic Experimental Studies Involving Humans (BESH) Announcements is Limited to Mechanistic Clinical Trials
  • NOT-MH-17-044 (August 17, 2017) - Notice of NIMH's Interest in Pediatric Pharmacologic Trials in Autism Spectrum Disorders, directed at testing selective GABAergic agents
  • NOT-MH-17-039 (July 24, 2017) - Notice of NIMH's Interest to Highlight High-Priority Pediatric Pharmacologic Trial Research Areas
  • NOT-MH-15-012 (March 17, 2015) - Data Sharing Expectations for Clinical Research Funded by NIMH
  • NOT-MH-15-009 (January 16, 2015) - Notice Announcing Data Harmonization for NIMH Human Subjects Research via the PhenX Toolkit
  • NOT-MH-14-015 (June 12, 2014) - Data Sharing Expectations for NIMH-funded Clinical Trials
  • NOT-MH-14-004 (January 15, 2014) - Enhancing the Reliability of NIMH-Supported Research through Rigorous Study Design and Reporting

Clinical Trials — Applicant FAQs

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